Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.
Female ; Mice ; Demethylation/drug effects* ; Embryonic Stem Cells ; Estrogens/administration & dosage* ; Gene Expression/drug effects* ; Histones/metabolism* ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Mice, Inbred C57BL ; Oocytes ; Ovary/drug effects* ; Reproductive Techniques, Assisted ; Animals

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Objective:To identify the spatial clustering and its temporal trends among newly reported HIV/AIDS cases in Henan Province during 1995-2020, and to provide evidence for strategies on prevention and control of the disease.Methods:Information about newly reported HIV/AIDS cases in Henan between 1995 and 2020 were obtained from China Information System for Disease Control and Prevention and to describe their demographic characteristics, spatial autocorrelation and changing trends. This program was conducted at county level, using the ArcGIS 10.2.Results:A total of 96 528 HIV/AIDS cases with complete current address information in counties (districts) were newly reported during 1995-2020 in Henan, and the spatial autocorrelation analysis showed that Global Moran's I index was 0.249, Z G value of the Global Getis-Ord G coefficient was 6.472 (all P<0.001), indicating that there was a high clustered positive spatial autocorrelation of HIV/AIDS. The newly reported HIV/AIDS cases from 1995 to 2000, 2001 to 2005, 2006 to 2010, 2011 to 2015, and 2016 to 2020 in Henan Province all exhibited high values of global spatial clustering. Their Moran's I indices were 0.197, 0.103, 0.491, 0.411 and 0.383, respectively. The Z G values of the Global Getis-Ord G coefficient were 4.580, 3.386, 10.246, 8.378 and 8.093, respectively. All of global spatial correlation were statistically significant (all P<0.001). The results of local spatial autocorrelation analysis showed that newly reported HIV/AIDS cases in Henan Province had high-high clustering areas at each time stage mentioned above. The number of high-high clustering counties/districts gradually increased from 6 in 2001-2005 to 21 in 2016-2020, spreading from Zhumadian City and Zhoukou City in southeast Henan to Nanyang City in southwest Henan, Zhengzhou City and its surrounding counties/districts in central Henan. Conclusions:In Henan Province, an increasing trend of clusters appeared on HIV epidemic among newly reported HIV/AIDS cases from 1995 to 2020, and high-high clustering areas gradually expanded from Zhumadian City and Zhoukou City to Nanyang City, Zhengzhou City and its surrounding counties/districts, indicating that it is necessary to strengthen the AIDS prevention and control programs in these areas in Henan.

A 82-year-old man was admitted to hospital with fever, unresponsiveness and elevated hypersensitive C-reactive protein, neutrophile granulocyte. Ceftriaxone was administrated by intravenous dripping in the emergency room, but the effect is not satisfied. Following his admission to the ward, anti-infection treatment started and antibiotics including cefoperazone sulbactam were given. Elizabethkingia meningoseptica was identified by blood culture and 16S rRNA sequencing. The lumbar puncture showed that cerebrospinal fluid pressure was 80 mmH₂O (1 mmH₂O=0.0098 kPa), and biochemical results were normal. After 11 days of anti-infection treatment, the patient was discharged with negative blood culture,and his hypersensitive C-reactive protein and neutrophile granulocyte declined. The patient received levofloxacin tablets for anti-infection treatment for 14 d after discharge, and no signs of infection were observed in three months' following up.

Objective:To analyze the epidemiological characteristics of newly reported HIV-infected cases aged 50 years and above in Henan province during 1995-2020, and to provide evidence for strategies on HIV/AIDS prevention and control.Methods:Information about newly reported HIV-infected cases aged 50 years and above in Henan between 1995 and 2020 were collected from the National Comprehensive HIV/AIDS Information System. The demographic and behavioral characteristics of HIV-infected cases aged ≥50 were analyzed, and the mixed linear model based on CD4 + T lymphocyte (CD4) counts back calculation was used to estimate the years, time and age of the HIV infection. Results:During 1995-2020, a total of 25 038 HIV-infected cases aged 50 years and above were newly reported, accounting for 25.8% (25 038/96 867) of the total number of newly reported HIV-infected cases in Henan. The proportion of newly reported cases over 50-years-old gradually increased from 4.5% (18/396) in 1995-2000 to 35.5% (9 666/27 239) in 2016-2020, with statistically significant difference ( χ2=3 105.53, P<0.001). Among them, the proportion of HIV-infected cases aged 60 years and above were increasing year by year. The proportion of male cases were increasing along with ageing. The proportion of HIV-infected cases detected by medical institutions also showed an upward trend. The newly reported HIV-infected cases aged 50 years and above were mainly transmitted through sexual contact. The proportion of heterosexual transmission increased from 5.5% (1/18) in 1995-2000 to 86.2% (8 334/9 666) in 2016-2020, and the proportion of MSM-behavior-related transmission increased from 0.0% in 1995-2000 to 13.5% (1 304/9 666) in 2016-2020. The majority of cases had extra-marital and/or non-commercial heterosexual behavior (48.1%, 4 007/8 334) and the proportion showed an upward trend. The majority of male cases had commercial heterosexual behavior (54.9%, 3 169/5 775), and with increasing proportion along with the increase of age. The majority of female cases had extra-marital and/or non-commercial heterosexual behavior (62.5%, 1 600/2 559), with increasing proportion of extra-marital and/or non-commercial heterosexual behavior. The proportion of heterosexual behavior with spouse or stable sexual partners showed a downward trend. The estimations based on CD4 counts back calculation model showed that among the newly reported HIV-infected cases aged 50 years and above, the average age being infected was (54.8±10.2) years, with 33.8% (4 263/12 621) infected before 50. The interval between infection and diagnosis was (5.7±6.2) years, of which 52.6% (6 636/12 621) were infected for 5 years or longer and 34.7% (4 384/12 621) were in the last 3 years. There was no linear correlation trend in the composition of infection years among the newly reported HIV-infected cases over 50-years-old. Conclusions:In Henan, from 1995 to 2020, the number of newly reported HIV-infected cases aged 50 years and above was increasing and sexual transmission becoming the main transmission route. The increase of prevalence was mostly seen in 60-years-old men, low education level and detected mainly by medical institutions. For this age group, the focus of HIV/AIDS prevention and control should target on those who were transmitted through extra-marital and/or non-commercial heterosexual, commercial heterosexual and MSM behavior and it is necessary to strengthen the HIV testing and detection in this population and in the elderly floating group.

Objective:To explore the incidence and risk factors of preoperative deep vein thrombosis (DVT) of elective total joint arthroplasty (TJA).Methods:Data of 500 patients before TJA from March 2015 to August 2016 who underwent ultrasound surveillance were retrospectively analyzed. All patients were divided into DVT group and non-DVT group according to results of ultrasound. Parameters including demographic data, basic medical history, and surgical information and laboratory indexes were collected. Risk factors were assessed via univariate, multivariate and logistic regression analysis.Results:Preoperative DVT was detected in 23 cases (4.6%, 23/500), all of which occurred in the intermuscular vein with no symptom, and among them there were 16 cases (5.6%, 16/285) before total knee arthroplasty and 7 cases (3.3%, 7/215) before total hip arthroplasty. Univariate analysis showed that age ( t=2.266, P=0.024), female patients ( χ2=4.028, P=0.045), history of hypertension ( χ2=7.907, P=0.005), D-dimer ≥0.5 μg/ml ( χ2=13.171, P < 0.001) were significantly higher than those in non-DVT group, and the differences were statistically significant. Multivariate analysis showed that D-dimer ≥0.5 μg/ml [ OR=6.655, 95% CI (1.929, 22.960), P=0.003] and history of hypertension [ OR=2.715, 95% CI (1.017, 7.250), P=0.046] were independent risk factors for preoperative DVT. Among them, the thrombus of 14 cases located in the operation side, 6 cases in non-operation side, and 3 cases in bilateral sides. Postoperative ultrasound showed that newly DVT occurred in 9 patients of whom 5 cases located in the contralateral muscular veins and 4 cases in the nearby muscular veins. After discharge, 22 patients (95.7%) with preoperative DVT were further evaluated by ultrasound. The average follow-up time was 3.0 months (range from 6 weeks to 9 months). The results showed that thrombus of 7 cases were completely dissolved, 13 cases were partially dissolved, and 2 cases remained unchanged. Thrombus extensions to proximal veins or symptomatic PE were not found. Conclusion:The incidence of preoperative DVT in patients with elective joint replacement was about 4.6%, among which D-dimer ≥0.5 μg/ml and history of hypertension were the risk factors for preoperative thrombosis.

Objective:To explore the relationship between insulin resistance, glucose and lipid metabolism related molecules and colorectal polyps.Methods:A total of 262 healthy people who underwent colonoscopy in Shandong cancer hospital from June 2019 to September 2020 were selected. The levels of serum vascular cell adhesion molecule-1 (VCAM-1), fibroblast growth factor 19 (FGF19), insulin like growth factor (IGF-1), fasting blood glucose and fasting blood insulin were detected by enzyme-linked immunosorbent assay (ELISA). Insulin resistance index (HOMA-IR) was calculated, and the influencing factors of occurrence, pathological type, size and number of polyps were analyzed.Results:Among 262 cases, 116 cases were polyp free, 113 cases were adenomatous polyp and 33 cases were inflammatory polyp. HOMA-IR, VCAM-1 and FGF19 in polyp group were 2.904±1.754, (334.415±139.573) ng/ml and (135.865±98.470) pg/ml, respectively, which were higher than 2.369±1.306, (302.480±99.946) ng/ml and(110.694±76.044) ng/ml in non-polyp group, respectively ( P<0.05). Multivariate Logistic regression analysis showed that the gender ( OR=4.269, 95% CI: 1.963-9.405) and FGF19 (77.0-131.4 pg/ml: OR=2.385, 95% CI: 1.155-4.926) were independent factors of colorectal polyps. The gender ( OR=3.799, 95% CI: 1.650-8.748) and FGF19 (77.0-131.4 pg/ml: OR=2.290, 95% CI: 1.072-4.891) were independent factors of colorectal adenomatous polyps. The gender( OR=6.725, 95% CI: 1.853-24.410) and fasting plasma glucose (≥6.5 mmol/L: OR=0.047, 95% CI: 0.009-0.245) were independent factors of colorectal inflammatory polyps. The gender ( OR=3.539, 95% CI: 1.293-9.689) was an independent factor for the occurrence of single polyp. The gender ( OR=5.063, 95% CI: 2.048-12.515), FGF19 (77.0-131.4 pg/ml: OR=2.502, 95% CI: 1.102-5.681), fasting plasma glucose (≥6.5 mmol/L: OR=0.282, 95% CI: 0.095-0.839) were independent factors of multiple polyps. The gender ( OR=3.416, 95% CI: 1.134-10.289) and fasting insulin (≥9.4 μU/ml: OR=9.480, 95% CI: 1.485-60.521) were independent risk factors for colorectal polyps<0.5 cm. The gender ( OR=3.151, 95% CI: 1.244-7.984) and fasting plasma glucose (≥6.5 mmol/L: OR=0.310, 95% CI: 0.102-0.941) were independent risk factors for colorectal polyps with the size of 0.5-0.9 cm. The gender ( OR=22.649, 95% CI: 4.154-123.485), age (55 to 64 years old: OR=4.473, 95% CI: 1.070-18.704; ≥65 years old: OR=5.815, 95% CI: 1.300-26.009), BMI (≥28 kg/m 2: OR=5.310, 95% CI: 1.224-23.032) and FGF19 (77.0-131.4 pg/ml: OR=7.474, 95% CI: 1.903-29.351) were independent factors for colorectal polyps with size ≥ 1.0 cm. Gender stratification analysis showed that FGF19 was an independent factor for the occurrence of male polyps (77.0-131.4 pg/ml: OR=6.109, 95% CI: 1.688-22.104) and adenomas (77.0-131.4 pg/ml: OR=6.401, 95% CI: 1.717-23.864). The age (55 to 64 years old: OR=3.783, 95% CI: 1.052-13.611) and VCAM-1 (≥352.8 ng/ml: OR=4.341, 95% CI: 1.142-16.493) were independent risk factors of female polyps. The age (55 to 64 years old: OR=5.743, 95% CI: 1.205-27.362, ≥65 years old: OR=6.885, 95% CI: 1.143-41.467), VCAM-1 (≥352.8 ng/ml: OR=6.313, 95% CI: 1.415-28.159) and IGF-1 (≥7.6 ng/ml: OR=5.621, 95% CI: 1.069-29.543) were independent factors of female adenoma. Conclusions:The occurrences of colorectal polyps and adenomatous polyps are related to insulin resistance and glucose and lipid metabolism. Serum FGF19 is an independent influencing factor for the occurrence of colorectal polyps and adenomatous polyps, and is a potential serological diagnostic marker and therapeutic target for colorectal polyps and adenomatous polyps.

Objective:To explore the relationship between insulin resistance, glucose and lipid metabolism related molecules and colorectal polyps.Methods:A total of 262 healthy people who underwent colonoscopy in Shandong cancer hospital from June 2019 to September 2020 were selected. The levels of serum vascular cell adhesion molecule-1 (VCAM-1), fibroblast growth factor 19 (FGF19), insulin like growth factor (IGF-1), fasting blood glucose and fasting blood insulin were detected by enzyme-linked immunosorbent assay (ELISA). Insulin resistance index (HOMA-IR) was calculated, and the influencing factors of occurrence, pathological type, size and number of polyps were analyzed.Results:Among 262 cases, 116 cases were polyp free, 113 cases were adenomatous polyp and 33 cases were inflammatory polyp. HOMA-IR, VCAM-1 and FGF19 in polyp group were 2.904±1.754, (334.415±139.573) ng/ml and (135.865±98.470) pg/ml, respectively, which were higher than 2.369±1.306, (302.480±99.946) ng/ml and(110.694±76.044) ng/ml in non-polyp group, respectively ( P<0.05). Multivariate Logistic regression analysis showed that the gender ( OR=4.269, 95% CI: 1.963-9.405) and FGF19 (77.0-131.4 pg/ml: OR=2.385, 95% CI: 1.155-4.926) were independent factors of colorectal polyps. The gender ( OR=3.799, 95% CI: 1.650-8.748) and FGF19 (77.0-131.4 pg/ml: OR=2.290, 95% CI: 1.072-4.891) were independent factors of colorectal adenomatous polyps. The gender( OR=6.725, 95% CI: 1.853-24.410) and fasting plasma glucose (≥6.5 mmol/L: OR=0.047, 95% CI: 0.009-0.245) were independent factors of colorectal inflammatory polyps. The gender ( OR=3.539, 95% CI: 1.293-9.689) was an independent factor for the occurrence of single polyp. The gender ( OR=5.063, 95% CI: 2.048-12.515), FGF19 (77.0-131.4 pg/ml: OR=2.502, 95% CI: 1.102-5.681), fasting plasma glucose (≥6.5 mmol/L: OR=0.282, 95% CI: 0.095-0.839) were independent factors of multiple polyps. The gender ( OR=3.416, 95% CI: 1.134-10.289) and fasting insulin (≥9.4 μU/ml: OR=9.480, 95% CI: 1.485-60.521) were independent risk factors for colorectal polyps<0.5 cm. The gender ( OR=3.151, 95% CI: 1.244-7.984) and fasting plasma glucose (≥6.5 mmol/L: OR=0.310, 95% CI: 0.102-0.941) were independent risk factors for colorectal polyps with the size of 0.5-0.9 cm. The gender ( OR=22.649, 95% CI: 4.154-123.485), age (55 to 64 years old: OR=4.473, 95% CI: 1.070-18.704; ≥65 years old: OR=5.815, 95% CI: 1.300-26.009), BMI (≥28 kg/m 2: OR=5.310, 95% CI: 1.224-23.032) and FGF19 (77.0-131.4 pg/ml: OR=7.474, 95% CI: 1.903-29.351) were independent factors for colorectal polyps with size ≥ 1.0 cm. Gender stratification analysis showed that FGF19 was an independent factor for the occurrence of male polyps (77.0-131.4 pg/ml: OR=6.109, 95% CI: 1.688-22.104) and adenomas (77.0-131.4 pg/ml: OR=6.401, 95% CI: 1.717-23.864). The age (55 to 64 years old: OR=3.783, 95% CI: 1.052-13.611) and VCAM-1 (≥352.8 ng/ml: OR=4.341, 95% CI: 1.142-16.493) were independent risk factors of female polyps. The age (55 to 64 years old: OR=5.743, 95% CI: 1.205-27.362, ≥65 years old: OR=6.885, 95% CI: 1.143-41.467), VCAM-1 (≥352.8 ng/ml: OR=6.313, 95% CI: 1.415-28.159) and IGF-1 (≥7.6 ng/ml: OR=5.621, 95% CI: 1.069-29.543) were independent factors of female adenoma. Conclusions:The occurrences of colorectal polyps and adenomatous polyps are related to insulin resistance and glucose and lipid metabolism. Serum FGF19 is an independent influencing factor for the occurrence of colorectal polyps and adenomatous polyps, and is a potential serological diagnostic marker and therapeutic target for colorectal polyps and adenomatous polyps.

With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.

Objective: Comparing the benefit of Abidor, lopinavir/ritonavir and recombinant interferon α-2b triple combination antiviral therapy and lopinavir/ritonavir and interferon dual combination antiviral therapy to hospitalized novel coronavirus pneumonia 2019 in Zhejiang province. Methods: A multi-center prospective study was carried out to compare the effect of triple combination antiviral therapy with dual combination antiviral therapy in 15 medical institutions of Zhejiang Province. All patients were treated with recombinant interferon α-2b (5 million U, 2 times/d) aerosol inhalation. 196 patients were treated with abidol (200 mg, 3 times/d) + lopinavir / ritonavir (2 tablets, 1 time/12 h) as the triple combination antiviral treatment group. 41 patients were treated with lopinavir / ritonavir (2 tablets, 1 time/12 h) as the dual combination antiviral treatment group. The patients who received triple combination antiviral therapy were divided into three groups: within 48 hours, 3-5 days and > 5 days after the symptom onset. To explore the therapeutic effects of triple combination antiviral drugs and dual combination antiviral drugs, as well as triple combination antiviral drugs with different antiviral initiate time. SPSS17.0 software was used to analyze the data. Results: The time of virus nucleic acid turning negative was (12.2 ± 4.7) days in the triple combination antiviral drug group, which was shorter than that in the dual combination antiviral drug group [(15.0 ± 5.0) days] (t = 6.159, P < 0.01 ). The length of hospital stay [12 (9, 17) d] in the triple combination antiviral drug group was also shorter than that in the dual combination antiviral drug group [15 (10, 18) d] (H = 2.073, P < 0.05). Comparing the antiviral treatment which was started within 48 hours, 3-5 days and > 5 days after the symptom onset of triple combination antiviral drug group, the time from the symptom onset to the negative of viral shedding was 13 (10,16.8), 17 (13,22) and 21 (18-24) days respectively (Z = 32.983, P < 0.01), and the time from antiviral therapy to the negative of viral shedding was (11.8±3.9) , (13.5±5.1) and (11.2±4.3) d. The differences among the three groups were statistically significant (Z=32.983 and 6.722, P<0.01 or<0.05). Conclusions The triple combination antiviral therapy of Abidor, Lopinavir/Litonavir and recombinant interferon α-2b showed shorter viral shedding time and hospitalization time compared with the dual combination antiviral therapy. The earlier the time to initiate triple antiviral treatment, the shorter the time of virus shedding.